Protein kinase CKII regulates the interaction of β-catenin withα-catenin and its protein stability

Bek, Stephan; Kemler, Rolf

doi:10.1242/jcs.00154

Cited by 82 publications

(71 citation statements)

References 54 publications

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“…4). Another group also recently found that mutation of Ser 29 reduced CK2 phosphorylation of ␤-catenin (69). In their system, Thr 102 and Thr 112 were also reported to be phosphorylated, although these data were not shown.…”

Section: Discussionmentioning

confidence: 93%

CK2 Phosphorylation of the Armadillo Repeat Region of β-Catenin Potentiates Wnt Signaling

Song

Domı́nguez

Mizuno

et al. 2003

Journal of Biological Chemistry

162

134

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Protein kinase CK2 is a ubiquitous serine/threonine kinase involved in many biological processes. It is overexpressed in many malignancies including rodent and human breast cancer, and is up-regulated in Wnt-transfected mammary epithelial cells, where it can be found in a complex with dishevelled and ␤-catenin. ␤-Catenin is a substrate for CK2 and inhibition of CK2 reduces levels of ␤-catenin and dishevelled. Here we report that inhibition of CK2 using pharmacologic agents or expression of kinase inactive subunits reduces ␤-catenindependent transcription and protein levels in a proteasome-dependent fashion. The major region of phosphorylation of ␤-catenin by CK2 is the central armadillo repeat domain, where carrier proteins like axin and the adenomatous polyposis coli gene product APC interact with ␤-catenin. The major CK2 phosphorylation site in this domain is Thr 393 , a solvent-accessible residue in a key hinge region of the molecule. Mutation of this single amino acid reduces ␤-catenin phosphorylation, cotranscriptional activity, and stability. Thus, CK2 is a positive regulator of Wnt signaling through phosphorylation of ␤-catenin at Thr 393 , leading to proteasome resistance and increased protein and co-transcriptional activity.Protein kinase CK2 is ubiquitously expressed in both the cytoplasm and nucleus of eukaryotic cells. It is highly conserved through evolution; mammalian CK2 can substitute for the yeast enzyme (1). CK2 functions as a tetramer assembled by homodimerization of two regulatory ␤ subunits followed by recruitment of two catalytic subunits (␣ or ␣Ј) (2-4). The catalytic subunits are highly homologous to each other but are encoded by different genes (5). Activity is regulated by the ␤ subunit, which confers some of the substrate specificity (6). In S. cerevisiae, deletion of either of the catalytic subunits results in a normal phenotype, but deletion of both leads to growth arrest (7). In mammals, the ␣Ј subunit is required for normal male germ cell development (8).CK2 is not known to be regulated by second messengers, but its activity is enhanced by polyamines and polylysines (9 -11) and inhibited by apigenin (chrysin) (12), 6-dichloro-1-␤-D-ribofuranosylbenzimidazole (13), and emodin (14). Biochemically, CK2 is unusual in that it is one of the few kinases that can efficiently utilize either ATP or GTP as the phosphoryl donor (15), a property that is very useful experimentally to identify its activity.CK2 phosphorylates serine or threonine in acidic domains, with S/TXXD/E being the canonical motif (16 -19). CK2 regulates many fundamental cellular processes. Of particular interest with respect to cancer biology, CK2 phosphorylates many transcription factors, proto-oncoproteins, and tumor suppressor proteins including c-Myc (20), Max (21), p53 (22), Mdm-2 (23), c-Jun (24), SV40 large T antigen (25), and others.CK2 phosphorylation can regulate DNA binding, e.g. for c-Jun (24) or Max (21) or nuclear translocation, e.g. for SV40 large T antigen (25). However, one of the important functions of CK2...

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Section: Discussionmentioning

confidence: 93%

CK2 Phosphorylation of the Armadillo Repeat Region of β-Catenin Potentiates Wnt Signaling

Song

Domı́nguez

Mizuno

et al. 2003

Journal of Biological Chemistry

162

134

View full text Add to dashboard Cite

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“…The integrity of this core protein complex is critical for the formation and maintenance of stable adhesions. Recent evidence, which remains somewhat controversial, indicates that there is cross-talk between the levels of β-catenin in the Wnt pathway with the more stable pools of β-catenin in adhesion complexes [43][44][45][46], findings which, with further clarification, may indicate that GSK3 has further influences on adhesion and migration through its regulation of β-catenin.…”

Section: Inflammation and Migration: Regulation By Gsk3mentioning

confidence: 99%

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

2006

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Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer's disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.

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“…␤-catenin can be modified by phosphorylation on either serine/threonine or tyrosine residues (Behrens et al, 1993;Bek and Kemler, 2002;Brembeck et al, 2004;Hoschuetzky et al, 1994;Nelson and Nusse, 2004;Piedra et al, 2001;Shiozaki et al, 1995;Sommers et al, 1994). In v-src-transformed MDCK cells, loss of cell-cell adhesion and increased invasiveness of the cells correlate with an increase in tyrosine phosphorylation of ␤-catenin (Behrens et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

Wingless signaling modulates cadherin-mediated cell adhesion inDrosophilaimaginal disc cells

Wodarz

Stewart

Nelson

et al. 2006

Journal of Cell Science

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Armadillo, the Drosophila homolog of β-catenin, plays a crucial role in both the Wingless signal transduction pathway and cadherin-mediated cell-cell adhesion, raising the possibility that Wg signaling affects cell adhesion. Here, we use a tissue culture system that allows conditional activation of the Wingless signaling pathway and modulation of E-cadherin expression levels. We show that activation of the Wingless signaling pathway leads to the accumulation of hypophosphorylated Armadillo in the cytoplasm and in cellular processes, and to a concomitant reduction of membrane-associated Armadillo. Activation of the Wingless pathway causes a loss of E-cadherin from the cell surface, reduced cell adhesion and increased spreading of the cells on the substratum. After the initial loss of E-cadherin from the cell surface, E-cadherin gene expression is increased by Wingless. We suggest that Wingless signaling causes changes in Armadillo levels and subcellular localization that result in a transient reduction of cadherin-mediated cell adhesion, thus facilitating cell shape changes, division and movement of cells in epithelial tissues.

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Protein kinase CKII regulates the interaction of β-catenin withα-catenin and its protein stability

Cited by 82 publications

References 54 publications

CK2 Phosphorylation of the Armadillo Repeat Region of β-Catenin Potentiates Wnt Signaling

CK2 Phosphorylation of the Armadillo Repeat Region of β-Catenin Potentiates Wnt Signaling

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

Wingless signaling modulates cadherin-mediated cell adhesion inDrosophilaimaginal disc cells

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